Chris Probert

Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial

Background: Pyoderma gangrenosum (PG) is a chronic ulcerating skin condition that often occurs in association with inflammatory bowel disease. There have been a number of reports of PG responding to infliximab, a monoclonal antibody against tumour necrosis factor α. Aim: In the first randomised placebo controlled trial of any drug for the treatment of PG, we have studied the role of infliximab in this disorder. Subjects: Patients 18 years of age or older with a clinical diagnosis of PG were invited to take part. Methods: Patients were randomised to receive an infusion of infliximab at 5 mg/kg or placebo at week 0. Patients were then assessed at week 2 and non-responders were offered open labelled infliximab. The primary end point was clinical improvement at week 2, with secondary end points being remission and improvement at week 6. Results: Thirty patients were entered into the study. After randomisation, 13 patients received infliximab and 17 patients received placebo. At week 2, significantly more patients in the infliximab group had improved (46% (6/13)) compared with the placebo group (6% (1/17); p = 0.025). Overall, 29 patients received infliximab with 69% (20/29) demonstrating a beneficial clinical response. Remission rate at week 6 was 21% (6/29). There was no response in 31% (9/29) of patients. Conclusions: This study has demonstrated that infliximab at a dose of 5 mg/kg is superior to placebo in the treatment of PG. Open label treatment with infliximab also produced promising results. Infliximab treatment should be considered in patients with PG.

Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial

Background: Tumour necrosis factor production is increased in the mucosa of patients with active ulcerative colitis. The benefits of infliximab in Crohn’s disease are established. We investigated its efficacy in ulcerative colitis. Methods: We conducted a randomised placebo controlled trial of infliximab (5 mg/kg) in the treatment of glucocorticoid resistant ulcerative colitis. Infusions were given at weeks 0 and 2. Disease activity and quality of life were recorded over eight weeks of follow up. Remission was defined as an ulcerative colitis symptom score (UCSS) of ⩽2 and/or Baron score of 0 at week 6. Patients not in remission were offered open label infliximab 10 mg/kg and reviewed two weeks later. Results: After two weeks, there was no statistically significant difference between the infliximab and placebo groups in the proportion of patients with a Baron score of 0 (13% (3/23) v 5% (1/19) (95% confidence interval (CI) −9% to 24%); p=0.74). After six weeks, remission (UCSS ⩽2) rates were 39% (9/23) versus 30% (6/20) (95% CI −19 to 34%; p=0.76). The median improvement in UCSS was 3 for the infliximab group and 2.5 for the placebo group (p=0.82, Mann-Whitney U test). A Baron score of 0 was likely in either group (26% (6/23) v 30% (6/20) (95% CI −30% to 23%); p=0.96). Improvement in the IBDQ and EuroQol was not significantly different between the groups (p=0.22 and 0.3, respectively, Mann-Whitney U test). Twenty eligible patients were given open labelled infusions. Remission was achieved in 3/11 (27%) patients initially treated with infliximab and in 1/9 (11%) patients treated with placebo. Conclusion: These data do not support the use of infliximab in the management of moderately active glucocorticoid resistant ulcerative colitis.

Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study

Background and aims: Oral aminosalicylates are well established in the treatment of active mild/moderate ulcerative colitis (UC) when the disease is extensive (that is, beyond the splenic flexure). The majority of clinical symptoms relate to disease activity in the distal part of the colon and therefore this study was designed to investigate if adding a mesalazine enema to oral mesalazine has additional benefit for patients with extensive mild/moderate active UC. Methods: A randomised double blind study was performed in 127 ambulatory patients. All received 4 g/day (twice daily dosing) oral mesalazine for eight weeks. During the initial four weeks, they additionally received an enema at bedtime containing 1 g of mesalazine or placebo. Disease activity was assessed using the ulcerative colitis disease activity index, with clinical and endoscopic signs at four and eight weeks. Results: Remission was obtained in 44% (95% confidence interval (CI) 31%, 58%) of the mesalazine enema group (Me) and in 34% (95% CI 21%, 49%) of the placebo enema group (Pl) at four weeks (p = 0.31) and in 64% (95% CI 50%, 76%) of the Me group versus 43% (95% CI 28%, 58%) of the Pl group at eight weeks (p = 0.03). Improvement was obtained in 89% (95% CI 78%, 96%) of the Me group versus 62% (95% CI 46%, 75%) of the Pl group at four weeks (p = 0.0008) and in 86% (95% CI 75%, 94%) of the Me group versus 68% (95% CI 53%, 81%) of the Pl group at eight weeks (p = 0.026). Conclusion: In patients with extensive mild/moderate active UC, the combination therapy is superior to oral therapy. It is safe, well accepted, and may be regarded as firstline treatment.

Fecal Microbiome and Volatile Organic Compound Metabolome in Obese Humans With Nonalcoholic Fatty Liver Disease

BACKGROUND & AIMS The histopathology of nonalcoholic fatty liver disease (NAFLD) is similar to that of alcoholic liver disease. Colonic bacteria are a source of many metabolic products, including ethanol and other volatile organic compounds (VOC) that may have toxic effects on the human host after intestinal absorption and delivery to the liver via the portal vein. Recent data suggest that the composition of the gut microbiota in obese human beings is different from that of healthy-weight individuals. The aim of this study was to compare the colonic microbiome and VOC metabolome of obese NAFLD patients (n = 30) with healthy controls (n = 30). METHODS Multitag pyrosequencing was used to characterize the fecal microbiota. Fecal VOC profiles were measured by gas chromatography-mass spectrometry. RESULTS There were statistically significant differences in liver biochemistry and metabolic parameters in NAFLD. Deep sequencing of the fecal microbiome revealed over-representation of Lactobacillus species and selected members of phylum Firmicutes (Lachnospiraceae; genera, Dorea, Robinsoniella, and Roseburia) in NAFLD patients, which was statistically significant. One member of phylum Firmicutes was under-represented significantly in the fecal microbiome of NAFLD patients (Ruminococcaceae; genus, Oscillibacter). Fecal VOC profiles of the 2 patient groups were different, with a significant increase in fecal ester compounds observed in NAFLD patients. CONCLUSIONS A significant increase in fecal ester VOC is associated with compositional shifts in the microbiome of obese NAFLD patients. These novel bacterial metabolomic and metagenomic factors are implicated in the etiology and complications of obesity.

Volatile organic compounds from feces and their potential for diagnosis of gastrointestinal disease.

Little is known about the volatile organic compounds (VOCs) in feces and their potential health consequences. Patients and healthcare professionals have observed that feces often smell abnormal during gastrointestinal disease. The aim of this work was to define the volatiles emitted from the feces of healthy donors and patients with gastrointestinal disease. Our hypotheses were that i) VOCs would be shared in health;ii) VOCs would be constant in individuals; and iii) specific changes in VOCs would occur in disease. Volatile emissions in health were defined in a cohort and a longitudinal study. Subsequently, the pattern of volatiles found in the cohort study were compared to that found from patients with ulcerative colitis, Campylobacter jejuni, and Clostridium difficile. Volatiles from feces were collected by solid‐phase microextraction and analyzed by gas chromatography/mass spectrometry. In the cohort study, 297 volatiles were identified. In all samples, ethanoic, butanoic, pentanoic acids, benzaldehyde, ethanal, carbon disulfide, dimethyldisulfide, acetone, 2‐butanone, 2, 3‐butanedione, 6‐Methyl‐5‐hep‐ten‐2‐one, indole, and 4‐Methylphenol were found. Forty‐four compounds were shared by 80% of subjects. In the longitudinal study, 292 volatiles were identified, with some inter and intra subject variations in VOC concentrations with time. When compared to healthy donors, volatile patterns from feces of patients with ulcerative colitis, C. difficile, and C. jejuni were each significantly different. These findings could lead the way to the development of a rapid diagnostic device based on VOC detection.—Garner C. E., Smith, S., de Lacy Costello B., White, P., Spencer, R., Probert, C. S. J., Ratcliffe N. M. Volatile organic compounds from feces and their potential for diagnosis of gastrointestinal disease. FASEB J. 21, 1675–1688 (2007)

Prevalence and family risk of ulcerative colitis and Crohn's disease: an epidemiological study among Europeans and south Asians in Leicestershire.

The family history of patients identified during incidence studies in Leicestershire were investigated and the prevalence and comparative risks calculated; 1254 patients aged 15 to 80 years were sent a questionnaire about their family history. All cases with a positive family history were reviewed and confirmed cases included in the study. In Europeans the standardised prevalence of Crohns disease was 75.8/10(5) and that of ulcerative colitis 90.8/10(5). The prevalence of Crohns disease among South Asians was 33.2/10(5) and that of ulcerative colitis 135/10(5). The prevalence of Crohns disease in Europeans was significantly greater than that in Hindus (chi 2 = 16, p < 0.001), while the prevalence of ulcerative colitis was significantly lower in Europeans than Hindus (chi 2 = 27, p < 0.001) and Sikhs (chi 2 = 4.4, p < 0.05). The comparative risk of developing ulcerative colitis in first degree relatives of Europeans patients with ulcerative colitis was increased by approximately 15, but the risk of Crohns disease was not increased. The comparative risk of developing Crohns disease among first degree relatives of patients with Crohns disease was increased by up to 35, the comparative risk of ulcerative colitis was approximately 3. The risk among relatives of South Asian patients with Crohns disease was not increased, but the risk of ulcerative colitis to relatives of patients with ulcerative colitis was. This study supports the view that Crohns disease and ulcerative colitis arise in people with a genetic predisposition and exposed to some, as yet unknown, environmental factor.

Diagnosis and treatment of pyoderma gangrenosum

Pyoderma gangrenosum is a rare but serious ulcerating skin disease, the treatment of which is mostly empirical. Pyoderma can present to a variety of health professionals and several variants exist that may not be recognised immediately. This can delay the diagnosis and have serious clinical consequences.1 The mainstay of treatment is long term immunosuppression, often with high doses of corticosteroids or low doses of ciclosporin. Recently, good outcomes have been reported for treatments based on anti-tumour necrosis factor α, and infliximab proved effective in a randomised controlled trial. This article reviews the presentation of pyoderma gangrenosum and the therapeutic options available. Fig 1 Classic pyoderma gangrenosum We used the keyword “pyoderma gangrenosum” to search Medline. We also searched the Cochrane database but found no Cochrane review on this disease. Several variants exist, but the most common one is classic pyoderma gangrenosum. This presents as a deep ulcer with a well defined border, which is usually violet or blue. The ulcer edge is often undermined (worn and damaged) and the surrounding skin is erythematous and indurated (fig 1). The ulcer often starts as a small papule or collection of papules, which break down to form small ulcers with a “cats paw” appearance. These coalesce and the central area then undergoes necrosis to form a single ulcer. Classic pyoderma gangrenosum can occur on any skin surface, but is most commonly seen on the legs. Patients are often systemically unwell with symptoms such as fever, malaise, arthralgia, and myalgia. Lesions are usually painful and the pain can be severe. When the lesions heal the scars are often cribriform. Early diagnosis and prompt treatment reduce the risk of scars, and disfigurement may occur if the diagnosis is missed.1 Pathergy occurs in 25-50% of cases—lesions develop at the site of minor trauma, so surgery or …

Basiliximab (anti-CD25) in combination with steroids may be an effective new treatment for steroid-resistant ulcerative colitis

Background : Steroid resistance represents a major clinical problem in the treatment of ulcerative colitis. In vitro, interleukin‐2 renders lymphocytes steroid resistant.

Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes

BACKGROUND Up to 29% of patients with severe ulcerative colitis (UC) fail to respond to steroid treatment and require surgery. Previous studies have failed to show a clear correlation between failure of steroid treatment in severe UC and measures of disease severity. The reasons for treatment failure therefore remain unknown. AIM To investigate the hypothesis that patients with severe UC who fail to respond to steroid treatment have steroid resistant T lymphocytes. METHODS Eighteen patients with severe UC were studied. After seven days’ treatment with high dose intravenous steroids they were classified as complete responders (CR), incomplete responders (IR), or treatment failures (TF). Within 48 hours of admission blood was taken and the antiproliferative effect of dexamethasone on phytohaemagglutinin stimulated peripheral blood T lymphocytes was measured. Maximum dexamethasone induced inhibition of proliferation (Imax) was measured. RESULTS In vitro T lymphocyte steroid sensitivity of TF and IR patients was significantly less than that of CR patients. Both TF and 3/5 IR patients had an Imax of less than 60%; all CR patients had an Imax of greater than 60%. No significant correlation was seen between response to treatment and disease severity on admission. When in vitro T lymphocyte steroid sensitivity was remeasured three months later, there was no difference between the groups. CONCLUSIONS Results suggest that T lymphocyte steroid resistance is an important factor in determining response to steroid treatment in patients with severe UC and may be more predictive of outcome than disease severity.

Basiliximab for the treatment of steroid‐resistant ulcerative colitis: further experience in moderate and severe disease

Preliminary data have suggested that interleukin‐2 receptor blockade with basiliximab may increase steroid sensitivity. We have previously reported a small case series demonstrating the potential of basiliximab as a novel agent for the treatment of steroid‐resistant ulcerative colitis.